The morbidity of chronic cardiovascular diseases in senile population has increased in the recent years. The most common chronic disease in senile population is hypertension.
Most of the effective methods for treating hypertension which have been developed as far relate to the inhibition of renin-angiotensin system (RAS), because RAS plays a central role in the regulation of blood pressure. In mammals, the elevation of blood pressure results from the production of an octapeptide hormone called angiotensin II in RAS from the cleavage of a decapeptide called angiotensin I by angiotensin converting enzyme (ACE). Accordingly, the inhibition of ACE provides a way for treating hypertension.
In the past twenty years, the most effective pharmaceuticals for hypertension therapy are ACE inhibitors, e.g. CAPOTEN.RTM. marketed by Bristol-Myers Co. and RENITEC.RTM. by Merck Sharp & Dohme Co.
The structural formulae of the active ingredients in the above products are depicted below: ##STR2##
ACE inhibitors, however, disadvantageously lack selectivity, and normally cleave other physiologically important peptides, causing side effects such as dry cough and vascular edema.
Another way for treating hypertension is to directly block the receptor of angiotensin II. Many peptide derivatives which mimic the action of angiotensin II are proposed for the antagonists of angiotensin II receptor. However, these peptide derivatives lack oral, exhibit partial agonist and lack long period of efficacy.
Recently, a more effective way for treating hypertension has been developed in the art, i.e. non-peptide antagonists of angiotensin II receptor. For example, the benzimidazole derivatives disclosed in U.S. Pat. No. 4,880,804; the oxadiazinone derivatives disclosed in U.S. Pat. No. 5,225,408; the imidazole derivatives described in EP-A 253 310; the quinoline derivatives disclosed in EP-A 412 848; the carbon-linked pyrazole derivatives disclosed in EP-A 446 062; the dihydropyrimidine derivatives disclosed in EP-A 547 442; the diphenylpyridinone derivatives disclosed in EP-A 542 059; and the condensed pyrazine derivatives disclosed in Japan Laid-Open Patent 5-155884. The above patents in their entirety are incorporated herein as the references of the invention.
Because the high morbidity of chronic cardiovascular diseases such as hypertension and congestive heart failure has increased in the recent years, developments of other novel non-peptide antagonists of angiotensin II receptor are of necessity.
One object of the invention is to provide novel non-peptide antagonists of angiotensin II receptor.
Another object of the invention is to provide a method for treating cardiovascular diseases, in particular hypertension and congestive heart failure.
A further object of the invention is to provide a pharmaceutical composition useful in the treatment of cardiovascular diseases, in particular hypertension and congestive heart failure.